Bleeding complications to oral anticoagulant therapy: multivariate analysis of 1010 treatment years in 551 outpatients

One thousand and ten patient years of oral anticoagulant therapy with vitamin-K-antagonists were reviewed with regard to major bleeding complications. The incidence of bleeding that necessitated hospital admission was 2.7% per year (95% confidence limits, 1.7-3.7%). The major source of bleeding was the alimentary tract, whereas no cases of intracranial bleeding were found. Various factors with potential effects on the bleeding risk were evaluated by multivariate statistical analysis, and the following independent risk factors were identified: age greater than 75 years and hypertension increased the bleeding risk by 10.5% and 4.5%, respectively. Each recorded prothrombin value significantly below the therapeutic range increased the bleeding risk by 3.9%, and each year of treatment increased the risk by 2.0%. These figures may be used to estimate the risk of major bleeding in an individual patient. Current treatment with thiazide diuretics was found to increase the bleeding risk by 5.2%. However, this observation requires further documentation and analysis. Although no lethal episodes of bleeding occurred, the developing field of indications for oral anticoagulant therapy should be considered on the basis of a continuous substantial risk of major bleeding.     

Hemorrhagic complications of oral anticoagulant therapy

Hemorrhage is the major complication of anticoagulant therapy. The criteria for classifying the severity of bleeding has varied between studies, which has resulted in variability in the rate of bleeding reported in the literature. The major determinants of oral anticoagulant-related bleeding are the intensity of the anticoagulant effect, baseline patient characteristics, and the length of therapy. Older patients have characteristics that may place them at higher risk for anticoagulant-related bleeding, but they also have characteristics that make them more likely to benefit. The risk for anticoagulant-related bleeding cannot be considered in isolation and the potential benefits need to be weighed carefully in each individual patient, irregardless of age.     

Age-related risks of long-term oral anticoagulant therapy

Long-term oral anticoagulant therapy is critical to the optimal management of various thromboembolic and vascular disorders. To determine whether age is related to the development of bleeding complications in patients who are receiving long-term oral anticoagulant therapy, the records of 321 patients who were followed up in the university hospital outpatient anticoagulation clinic during an eight-year period were reviewed. During this period, 61 patients (19%) developed minor bleeding complications, and 14 patients (4.4%) developed major bleeding complications. In utilizing a life-table approach to adjust for varying lengths of follow-up, the risk of initial minor bleeding complications was found to be greatest within the first three months (14%). For major bleeding complications, risk increased throughout the first two years of anticoagulation clinic follow-up, with no particular period of greatest risk. No significant differences in the risk of initial minor or major bleeding complications were observed in the various age groups that were examined (less than 50, 50 to 59, 60 to 69, and greater than or equal to 70 years). A multivariate regression approach, controlling for several potentially confounding factors, confirmed the lack of an association of age with the risk of minor or major bleeding complications. The results of this retrospective follow-up study suggest that patient age, in and of itself, should not be considered a primary factor in assessing the risk of long-term oral anticoagulant therapy.     

Current challenges and future prospects in oral anticoagulant therapy

The choice for oral anticoagulant (OAC) therapy was previously limited to the vitamin K antagonists (VKAs). The advent of the direct oral anticoagulants (DOACs) brought with it the expectation that oral anticoagulation would become simpler (with the elimination of routine monitoring and introduction of a fixed‐dose anticoagulant), and that the use of VKAs would be slowly phased out. Although DOACs have made anticoagulation more convenient and accessible, we are now faced with what can be described as a tyranny of choice, together with many unanswered questions relating to DOAC use. These include optimal DOAC selection and dosing, use in complex ‘real‐world’ patients, the role for monitoring and issues surrounding adherence. Warfarin remains the anticoagulant of choice in certain scenarios (e.g. metallic heart valves). The future holds much excitement: clinical studies are underway to expand the indications for DOACs and experience continues to grow outside the trials setting.     

Bleeding risk index in an anticoagulation clinic

BACKGROUND: The Outpatient Bleeding Risk Index (BRI) prospectively classified patients who were at high, intermediate, or low risk for warfarin-related major bleeding. However, there are only 2 published validation studies of the index and neither included veterans. OBJECTIVE: To determine the accuracy of the BRI in patients attending a Veterans Affairs (VA) anticoagulation clinic and to specifically evaluate the accuracy of the BRI in patients with atrial fibrillation. DESIGN: Retrospective cohort study. PATIENTS AND MEASUREMENTS: Using the BRI, all patients managed by the Anticoagulation Clinic between January 1, 2001 and December 31, 2002 were classified as high, intermediate, or low risk for major bleeding. Bleeds were identified via quality-assurance reports. Poisson regression was used to determine whether there was an association between the index and the development of bleeding. RESULTS: The rate of major bleeding was 10.6%, 2.5%, and 0.8% per patient-year of warfarin in the high-, intermediate-, and low-risk groups, respectively. Patients in the high-risk category had 14 times the rate of major bleeding of those in the low-risk group (incidence rate ratio (IRR) 14; 95% confidence interval (CI), 1.9 to 104.7). The rate of major bleeding was significantly different between the high- and intermediate-risk categories (P<.001). Among those with atrial fibrillation, patients in the high-risk category had 6 times the major bleeding rate of those in the intermediate- and low-risk groups combined (IRR=6; 95% CI, 2.4 to 15.3). CONCLUSIONS: The BRI discriminates between high- and intermediate-risk patients in a VA anticoagulation clinic, including those with atrial fibrillation.     

Haemorrhagic and thromboembolic complications in patients with atrial fibrillation on anticoagulant prophylaxis

We studied clinically relevant haemorrhagic and thromboembolic events in 213 patients with atrial fibrillation (AF) during 818 patient-years of anticoagulant (AC) treatment. The incidence of complicating events per 100 patient-years of treatment in three groups of patients, those with mitral valve disease (MVD; n = 34), without MVD (n = 102) and those with previous thromboembolism (TE; n = 77) was: major peripheral haemorrhages 3.1, 3.3 and 8.2 (non-MVD vs. TE group, P less than 0.05), cerebrovascular events 3.9, 3.0 and 3.0 (NS), and peripheral arterial thromboembolism 0, 0 and 1.5 (non-MVD vs. TE group, P less than 0.05). The proportion of thrombotest values less than 5 and/or greater than 20% at regular check-ups was 9.8% in patients with and 6.9% in patients without major peripheral haemorrhages (P less than 0.01). Major peripheral haemorrhages are frequent in patients with AF receiving AC treatment. They are most likely to occur in those with previous thromboembolism and among those with unstable AC control.     

Evaluation of protein C and protein S levels during oral anticoagulant therapy

A number of workers have examined protein C in relation to other vitamin K dependent factors during warfarin therapy and successfully identified protein C deficient patients by ratio calculation. However, protein S deficiency has not been addressed in this manner. This study compares protein C and protein S by functional and antigenic determination with procoagulant factors of similar half life (Factors VII and II) in an attempt to identify protein C and protein S deficient patients whilst on oral anticoagulant therapy. Procoagulant and anticoagulant factors were compared by linear regression in a population of normal blood donors and patients on stabilized warfarin therapy to obtain expected values for protein C and protein S dependent upon FVII and FII levels, respectively. Observed over expected values for protein C and protein S were calculated for individual patients and normal ranges derived. Comparison of similarly calculated observed over expected protein C and protein S ratios with these normal ranges successfully identified known protein C and protein S deficient patients who were taking warfarin at time of testing.     

肺动脉血栓栓塞抗凝治疗的临床研究

目的探讨肺栓塞患者抗凝治疗的有效性和安全性。方法对108例确诊的肺栓塞患者进行常规抗凝治疗,早期静脉应用普通肝素24小时,之后应用低分子肝素皮下注射5天～12天,肝素治疗第1天开始重叠应用华法林共3天～5天,此后单独应用华法林,并进行随访1年。结果108例肺栓塞患者进行抗凝治疗后,临床症状和影像学异常得到有效改善。随访期间,全部患者中近控5例,显效39例,好转45例,无效6例,恶化4例,死亡9例,总有效率82.4%。9例死亡患者有7例死于发病后14天内。华法林长期抗凝后可减少复发。结论肺栓塞患者应用普通肝素、低分子量肝素和口服华法林抗凝治疗安全有效;口服华法林宜从3mg开始,维持量3mg～4mg以达到理想INR目标值（2.0-3.0）。     

Rebound after cessation of oral anticoagulant therapy: the biochemical evidence

The existence of a phenomenon of rebound hypercoagulability after cessation of oral anticoagulant therapy is controversial. The sensitive procoagulant markers for in vivo thrombin and fibrin formation are potential tools for the reassessment of the presence of such a phenomenon. We examined 19 patients anticoagulated for 6 ± 2 months (SD, range 3–12) because of venous thromboembolism or myocardial infarction as follows: twice during stable, oral anticoagulation (INR 3.1–3.7) and then on days 1, 2, 3, 4, 5, 7, 9, 11, 13, 15 and >30 after cessation of oral anticoagulation. Thrombin–antithrombin III complexes (TAT) and fibrinopeptide A (FPA) were measured in addition to the prothrombin times and factors II, V, VII, and X. None of the 19 patients developed clinically manifest thromboembolism within the following 9–18 months. However, the patients' TAT levels increased transiently: rising from 1.5 ± 0.1 ng/ml (SEM) to 3.0 ± 0.2 ng/ml on day 4 ( P  < 0.001), and returned to 1.7 ± 0.1 ng/ml after day 30 (normals 1.8 ± 0.33). 17/19 patients showed TAT peak levels above the upper limit of normal between days 3 and 11 (average: day 4), which normalized again after 30 d. 8/19 patients also had transient FPA levels above the upper normal limits (<1.81). We conclude that our patients increased their thrombin and fibrin formation transiently and that a subpopulation reached values consistent with a prethrombotic state.     

Acquired coagulopathy caused by intoxication with the superwarfarin-type anticoagulant rodenticide flocoumafen

A 28 year-old heretofore healthy woman was transferred to our hospital with a two-month history of recurring episodes of bleeding. Administration of vitamin K and prothrombin complex concentrates in the transferring hospital had only temporarily corrected both the markedly elevated international normalized ratio (INR) and the prolonged activated partial thromboplastin time (aPTT). The patient's medical and family history revealed no reason for these abnormalities. Our laboratory analyses revealed a sustained deficiency of vitamin K-dependent clotting factors. Presence of an acquired inhibitor of clotting factors was excluded. Thus we suspected, intoxication with an anticoagulant rodenticide. Liquid chromatography-mass spectrometry (LC-MS/MS) revealed pharmacologically active concentrations of flocoumafen, a rodenticide belonging to the superwarfarin family, in the patient's serum. While the long elimination half-life of superwarfarins is well described in rodents, information on pharmacokinetics in humans is not yet available. Therefore, patient management was not limited to prolonged administration of vitamin K, but also included repeated measurements of flocoumafen serum levels. During follow-up visits, clotting tests remained normal and flocoumafen levels gradually decreased, reaching the limit of quantification after 48 days. Based on the repeated measurements of flocoumafen serum levels, a half-life of 6.7 days was estimated in our patient, which is in clear contrast to the 220 days reported in rodents. Thus, monitoring flocoumafen serum concentrations in affected patients may provide a rational basis for the duration of vitamin K substitution and adequate follow-up intervals.     

Lone atrial fibrillation and anticoagulant therapy

Assessment of risk of thromboembolism and potential benefit of prophylaxis with long-term anticoagulant therapy in lone atrial fibrillation is hampered by a lack of consensus regarding definition of lone atrial fibrillation. In general, patients less than 60 years of age with normal left ventricular function and left atrial size have a low risk of thromboembolic events and are unlikely to gain any significant benefit with anticoagulants; however, patients older than 60 years with impaired left ventricular function, enlarged left atrium, and/or associated conditions such as hypertension have an increased risk of thromboembolism and would benefit from long-term anticoagulant therapy. Decisions regarding anticoagulant usage would be simplified by using a scoring system containing clinical and investigational variables.     

Pulmonary thromboembolism with massive vaginal bleeding due to thrombolytic therapy

Thrombolytic therapy may reduce the morbidity of pulmonary thromboembolism (PTE) and the risk of recurrent disease. The most important complication of thrombolytic therapy is bleeding. We report a patient with PTE complicated by massive vaginal bleeding due to thrombolytic therapy.     

Recurrent thromboembolism,bleeding, and mortality in Asian patients with venous thromboembolism receiving different oral anticoagulants: A nationwide analysis

Venous thromboembolism (VTE) is associated with a high risk of morbidity and mortality. However, data on the association between oral anticoagulants and the hazards of VTE complications in Taiwanese patients with VTE is limited. This study aimed to compare the hazards of recurrent VTE, bleeding, and mortality between patients with VTE receiving rivaroxaban, a non-vitamin K antagonist oral anticoagulant (NOAC), and those receiving heparin or low-molecular-weight heparin (LMWH) followed by warfarin. Patients with VTE treated with rivaroxaban, or heparin or LMWH followed by warfarin were enrolled from 2 million random samples from Taiwan’s National Health Insurance database between 2013 and 2016. Hazards of recurrent VTE (deep vein thrombosis and pulmonary embolism), major bleeding, and mortality in rivaroxaban and warfarin users were investigated. Survival analyses were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Users of rivaroxaban (183) and warfarin (456) were included in the study. Patients receiving rivaroxaban did not have significantly lower hazards of developing recurrent VTE (HR, 0.72 [CI, 0.37–1.37], P = .31) and mortality (HR, 0.86 [CI, 0.49–1.50], P = .59) than those receiving heparin or LMWH followed by warfarin. In addition, the hazard ratio of major bleeding was not significantly different between the 2 regimens (HR, 1.80 [CI, 0.39–8.29], P = .45). Rivaroxaban was not associated with lower risks of recurrent VTE and mortality and higher hazards of major bleeding than heparin or LMWH followed by warfarin in Taiwanese patients with VTE. Clinicians may tailor oral anticoagulants for VTE patients according to the patient’s characteristics, cost-effectiveness and healthcare system policy.     

华法林出血并发症相关药物基因组学研究进展

华法林作为一线口服抗凝药广泛应用于血栓栓塞性疾病的预防与治疗中,但如何安全有效地应用华法林并达到最佳抗凝效果,一直是临床上亟待解决的难题。近年对华法林药物基因组学的研究表明,华法林代谢和作用相关基因(CYP2C9、VKORC1、CYP4F2)的变异很大程度上影响华法林的治疗剂量,还可能与华法林的出血并发症密切相关。本文对上述基因变异与华法林的过度抗凝及出血的相关研究作一综述,以期为临床华法林的个体化抗凝治疗提供参考依据。